Issues With Clinical Trials That Impede New Pain Drug Development

Pre-clinical animal efficacy studies do not accurately predict human efficacy, and clinical trials often inaccurately fail to show drug efficacy.

The National Academies of Sciences, Engineering and Medicine held a day-long workshop early November, dealing with “Regulatory strategies to address prescription opioid-related harms,” as part of a series organized by a committee of the same name at the Academies.

One of the presentations given at this workshop, titled “Accelerating the Development of Better Treatments for Pain: Notes From the Drug Development Battlefield,” was delivered by Nathanial Katz, MD, MS, an adjunct assistant professor of Anesthesia at Tufts School of Medicine.1

Dr Katz is also the president of Analgesic Solutions, a company both consulting on and conducting clinical trials, which he founded “with the mission of modernizing the design and conduct of pain clinical trials to advance the ‘scientific quality' of pain clinical research, and empower effective treatments for patients.”

A neurologist by training, Dr Katz held previous positions as a pain management specialist at Harvard Medical School, Brigham & Women's Hospital and at Dana Farber Cancer Institute, taking care of patients with acute, chronic and cancer pain. He also served from 2000 to 2004, as chair of the Advisory Committee, Anesthesia, Critical Care, and Addiction Products Division at the Food and Drug Administration (FDA).

Dr Katz announced the premise for his presentation: “We are not going to work our way out of [the prescription opioid abuse issue] as long as we do not have any better treatments for pain and the opioids. What are we doing to develop better treatments for pain, and how can we do that better?” There is a need to develop safer opioids as well as non-opioid treatments for pain, he added.

In an endeavor to accelerate the development of such treatments, the FDA launched the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT),now known as the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION).2 This public-private partnership facilitates interactions between the FDA and key stakeholders, with the goal of improving the way in which clinical trials for pain treatments are conducted, accelerate the process, and get more reliable information and data from those trials.

This initiative has sought to address the numerous methodological challenges commonly associated with clinical trials, by issuing guidance documents that have proven most valuable to the pharmaceutical industry. “We do not have a single example of a treatment for pain that has been rationally developed the normal way through animal models and pre-clinical testing, and human clinical trials,” noted Dr Katz.

All the treatments that are available to manage pain are either age-old ones, derived from plants (eg, opioids, non-steroidals), or medications developed for other conditions (eg, epilepsy, depression), and were then accidentally found to be effective for pain, pointed Dr Katz. “Why have we not been more successful at developing better treatments for pain?” he asked.

According to him, drug development faces 2 major issues: pre-clinical animal efficacy studies do not accurately predict human efficacy, a major issue, as translation into humans is the whole raison d'être of drug development. Secondly, because of the way in which clinical trials are conducted, these frequently fail to show drug efficacy, despite the fact that other studies indicate otherwise. So one might ask the following question: how can we develop a drug, when we cannot conduct reliable clinical trials?

Showing a list of New Molecular Entities (NMEs) that include NMDA and glycine antagonists, opioid-NMDA combinations, GABA agonists, cannabinoids and anti-NGF antibodies, which entered phase IV clinical trials in the past few years, Dr Katz sought emphasize the fact that, because of safety or lack of efficacy issues, “None of these drugs are on the market…We need to clean up how we do clinical trials,” he said.

Modern science, and drug development in particular, is facing a reproducibility crisis.2-4 In 2 studies, conducted by Amgen Inc. and Bayer AG, researchers were only able to reproduce 11% and 25%, respectively of published findings from landmark studies, calling for concern on the validity of preclinical basic science studies.5,6

To address this concern of non-reproducibility, the ACTTION group has issued recommendations applicable for pain studies.2 In the same vein, the online open access publishing platform, F1000Research, dedicated to provide “immediate and transparent publishing,” launched a Preclinical Reproducibility and Robustnesschannel, as a way to “provide a centralized space for researchers to start an open dialogue, thereby helping to improve the reproducibility of studies.”

Renowned biochemist, Bruce Alberts, PhD, professor in the Department of Biochemistry and Biophysics at the University of California, San Francisco, former president of the National Academy of Sciences, and recipient of numerous awards that include the National Medal of Science, serves as an advisor for this channel, which offers a platform for scientists, to either confirm or report the failure to do so, of published data.

A starting point, according to Dr Katz, would be to request preclinical efficacy data – a step he has taken for the past 3 years, which led him to realize that in most cases, those studies are fraught with major flaws. He cited various observed scenarios, which included studies never actually conducted, to reports either missing or in an unacceptable format, to inadequate quality control, selective data reporting, inability to account for animals used in the study, to fabrication of data or methods (eg, lack of blinding or randomization).